Study of the effects of cancer on the skeleton has represented a multi-departmental and multidisciplinary area of research at UTHSCSA for over twenty years. This collaborative effort has resulted in significant research breakthroughs and successful applications for external funding by the participating investigators. While there has been an NCI PO1 grant active continuously at UTHSCSA since 1986 on "Effects of Tumors on the Skeleton," this group has also had NCI-funded grants on this topic since 1976. In addition, through these efforts, UTHSCSA has become well known nationally and internationally as a center for studies on this topic. Studies funded by this grant have led to the current animal models used to study manifestations of bone metastasis, have identified new therapeutic modalities, and determined many of the basic mechanisms responsible for interactions between cancer cells and the bone microenvironment, which has fundamentally changed how the metastatic process in general is viewed, and in particular the role of the bone microenvironment in this process, as exemplified by the "vicious cycle", a concept derived from work coming from this PO1 during the last grant period. This grant has been responsible for publications in Science, Nature, J Clin Invest, J Cell Biol, PNAS, and NEJM, and 138 papers alone in the most recent grant period. During the last funding cycle, two of the project leaders left the institution to start their own large independent programs. Although these investigators stay closely affiliated, this natural attrition has allowed the opportunity for us to recruit outstanding new investigators to the program and markedly expand our research breadth and approaches into completely new areas such as proteasome biology in cancer bone disease, and the potential of TGF/ff antagonists to reduce bone metastasis and the mechanisms responsible. During the next funding period, our objectives are to identify novel molecular mechanisms responsible for important manifestations of cancer on the skeleton, including mechanisms responsible for the stimulatory effect of TGF/8 on PTH-rP expression and subsequent osteolysis, regulation of expression of the bone resorbing peptide PTH-rP by breast cancer cells, molecular interactions between TGF/S and its receptor on breast cancer cells, and the role of the ubiquitin-proteasome pathway in myeloma progression and the associated bone disease. We believe that these studies should have practical consequences in the identification of molecular targets for rational new drug discovery in this field.